Two genes control the activity of five isozymic forms of the synaptically active enzyme acetylcholinesterase (AChE) in the nematode Caenorhabditis elegans. Mutants with defects in either of these genes are behaviorally and developmentally normal, but the double mutant, which has only 2% of wild type AChE activity, has an uncoordinated (Unc) phenotype characterized by a hypercontraction and temporary paralysis of the musculature induced by mechano-sensory stimuli. Genetic, behavioral and biochemical studies suggest that at least two genetically distinct forms of AChE function in the same synapses or neuromuscular junctions. Stains for AChE in whole amounts of wild type and AChE-deficient mutants are consistent with this interpretation. We plan to isolate additional AChE mutants which will be characterized behaviorally, genetically, histochemically, biochemically and ultrastructurally. These mutants should be useful for establishing the molecular and subunit structure of isozymic forms of AChE; the control of AChE synthesis, activity and localization; and the role of AChE and acetylcholine in the development and maintenance of the extremely simple nervous system of C. elegans. We also plan to use the behavioral phenotype of double mutants and an AChE mutant-specific developmental defect induced by the AChE inhibitor Aldicarb to isolate revertants of the AChE defects. Some of these revertants should harbor mutations in other components of the synapses. The identification of these components and their role in the development and maintenance of the nervous system will be of interest. A full understanding of the genetic and molecular mechanisms responsible for functional synapse formation and maintenance in an experimental model system such as C. elegans will be important in understanding and correcting disruptions of these processes which occur in neurological disease.